4, 9 dihalo androstene compounds



3,014,937 4,9 DHEALO ANDROSTENE COMPUUNDS Howard 3. Ringold and Fred A. Kincl, Mexico City, Mexico, assignors to Syntax S.A., Mexico City, Mexico,

a corporation of Mexico N Drawing. Fiied Dec. 219, 1958, Ser. No. 783,083

Claims priority, appiication Mexico Jan. 13, 1958 9 Claims. (Cl. 256-69145) The present invention relates to cyclopcntanophenanthrene derivatives. More particularly the present invention relates to novel 17oz lower alkyl-4,9-dihaloo -androsten l7;8-ol-3-one compounds having an ll-keto group or an llfi-hydroxy group and wherein the 4-halo group is chlorine or bromine and the 9-hal0 group is chlorine, bromine or fluorine. These novel 17a-lOW6I' alkyl compounds and especially the 17-metl1yl derivatives are hormones of the androgenic type having an especially marked anabolic efiect. v

The novel compounds of the present invention are illustrated in general by the following formula:

wherein R is =0 01' R is lower alkyl such as methyl, ethyl or propyl and most desirably methyl, X is bromo, chloro or fluoro and Y is chloro or bromo.

The novel compounds are prepared by a process illustrated by the following equation:

OH OH hydrobromic l hydrochloric or acid hypobromous acid 3,014,937 Patented Dec. 26, 1951 EQQ l hydrochloric or chromici hydrofluoric acid acid// In the above equation X, R and Y represent the same groups as heretofore and X represents chloro or bromo.

l7a-methyl-A -androstadien l7 3-ol-3-one (Herr et -al., J. Am. Chem. Soc, 78, 500 (1956)) was treated with concentrated hydrogen peroxide, preferably in methanol solution in the presence of aqueous sodium hydroxide solution, and thus there was obtained 17amethyl 4,8,5l8-oxide-A randrosten l7fi-cl-3-one. By reaction of the latter with concentrated hydrochloric or hydrobromic acid, for example in acetone solution, there was produced the corresponding l7tx-methyl 4 halo- A -androstadien-17,8-ol-3-one which in turn was allowed to react with hypobrornous acid to produce the respective 17a-methyl-4-halo 9oz bromo-M-androsten- 1lfl,l7fi-dio1-3-one; preferably thisreaction was effected by treatment of the steroid in dioxane solution with N-bromoacetamide and perchloric acid.

In order to substitute the bromine atom at C-9a with chlorine or fluorine, there was prepared l7a-methyl-4- halo-9,8,1lB-oXi'do-A androstcn-17,8-01-3-one by reaction of the 4-halo-9w'bromo-M-androsten-11,6,17B-diol-3-one with potassium acetate, for examplel inmethanol solution. The epoxide ring was then opened by reaction with 7 Example I To a solution of 1O g. of '17a-methy1-A -androstadie-n-175-ol-3-one in 300 cc. of methanol there was added 60 cc. of concentrated hydrogen peroxide solution followed by 20 cc. of cold 10% sodium hydroxide solution, which were added slowly under stirring and maintaining the temperature of the mixture below 20 C. After standing for 48 hours, the mixture was poured into water and extracted with methylene: dichloride. The extract was washed with water to neutral, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crystallization of the residue from acetone afforded l7a-methyl-4fl,5fl-oxido-A -androsten 176- ol-3-one.

A solution of 8 g. of the above compound in 80 cc. of acetone was treated with 8 cc. of concentrated hydrochloric acid, slowly and under stirring, and the mixture was kept at room temperature for 1 hour. It was then diluted with ice water until it became turbid and kept overnight in the refrigerator. The precipitate formed was collected, thus giving 17m-methyl-4-chloro-A androstadien-l7fi-ol-3-one.

To a solution of g. of the above compound in 250 cc. of dioxane containing 45 cc. of water there was added under continuous stirring 750 mg. of N-bromoacetamide and then 45 cc. of 0.8 N perchloric acid, in the course of 5 minutes. The mixture was stirred for minutes longer, poured into 500 cc. of 10% sodium bisulfite solution and then ice and sodium chloride were added. The precipitate was collected, washed with Water and dried. There was thus obtained the crude Not-methyl- 4-chloro 90c bromo-M-androsten 11,8,17/3-diol-3-one. The pure substance was obtained by recrystallization from acetone.

A stirred solution of 5 g. of the above compound in 250 cc. of 90% acetic acid was slowly treated at room temperature with a solution of 1.2 equivalents of chromium trioxide in 25 cc. of 80% acetic acid. The mixture was kept at room temperature for 1 hour and then diluted with water to precipitate the 17m-methyl-4-chloro- 9a-bromo-A -andr0sten-l75-ol-3,ll-dione formed, which was collected by filtration, washed with Water and purified by recrystallization from methanol.

Example II In another experiment, in accordance with the method of Example I, the reaction of 17a methyl- 4 3,513- oxido-A -androsten-17,8-ol-3-one was carried out with concentrated hydrobromic acid instead of hydrochloric acid, thus giving rise to the formation of 17u-methyl-4- bromo-A -androstadien-17,9-ol-3-one. There were then obtained 11,8,17fi-diol-3-one and l7ot-methyl-4,9a-dibrorno-A -androsten- 1713-01-3, 1 l-dione.

Example III 17u-methyl-4,9'e-dibrorno-A androsten- The above crude compound was dissolved in cc. of methylene dichloride in a polyethylene container and cooled to 0 C. The solution was then treated with 8 cc. of 50% aqueous hydrofluoric acid, which was added slowly, with vigorous stirring and maintaining the temperature at around 0 C. The stirring was continued at a temperature around 0' C. for 6 hours and then water was added. The organic layer was separated, washed with water to neutral and concentrated to a small volume. The residue was treated with hexane and cooled, thus producing the crystalline 17a-methyl-4-chloro-9rxfluoro-M-androsten-l1fi,17!3-diol-3-one, which was filtered, washed and dried.

By the same method described in Example I, there was oxidized the llfi-hydroxyl group of this compound to the keto group, thus yielding I7a-mCthY1-4-Chl0fO-9ozfiuoro-M-androsten-l7,6-01-3,1 l-dione.

Example IV By the method of the previous example, 17a-methyl-4- memo-9,8,1lfi-oxido-A -androsten-175-01-3-0ne was converted into l7oz-methyl-4-bromo-9a-fluoro-A -androsten- 115,17fi-diol-3-one, which was then converted into one.

- Example V By substituting in the method of Examples III and IV the concentrated hydrofluoric acid by concentrated hydrochloric acid, there were obtained: l7a-methyl-4,9adichloro A -androsten-l15,1713-diol-3-one, 17u-methyl- 4,9a-dichlor0-A -androsten 1719 ol 3,11 dionc, 17amethyl-4-bromo-9u-chloro-A androsten 115,176 diol- 3-one and l7a-methyl-4-bromo-9a-chloro-A"-androsten 1713-01-3 l l-dione, respectively.

We claim:

1. l7a-rnethyl-4,9a-dibromo A -androsten-11 5,17B- diol-3-one.

2. 17cx-methyl-4-bromo-9a-chloro M-androsten-llfi; 17fl-diol-3-one.

3. 17a-rnethyl-4-bromo-9a-fiuoro A -androsten-11fl- 17,3-diol-3-one.

4. 17a-methyl-4,9u-dichloro A androsten-l7 3-ol-3- ll-dione. v

5. 17a-methyl-4-chloro-9a-bromo A -androsten-17fiol-3,11-dione.

6. 17m-methyl-4-chloro-9a-fiuoro A -androsten-17flol-3,11-dione.

7. l7a-methyl-4,9a-dibromo A -androsten-17fi-0l-3,- ll-dione.

8. 17a methyl-4-bromo-9a-chloro M-androsten-Ufiol-3,11-dione.

9. 17a-methyl-4-bromo-9a-fluoro A androsten-Uflol-3,11-dione.

References Cited in the file of this patent UNITED STATES PATENTS Herr Feb. 21, 1956 Herr May 21, 1957 

1. 17A-METHYL-4,9A-DIBROMO -$4-ANDROSTEN-11B,17BDIOL-3-ONE.
 4. 1MA-METHYL-4,9A-DICHLOR-$4-ANDROSTEN-17B-01-311-DIONE. 